Interleukin (IL)-1β is a culprit of adipose tissue inflammation, which in turn causes systematic inflammation and insulin resistance in obese individuals. IL-1β is mainly produced in monocytes and macrophages and marginally in adipocytes, through cleavage of the inactive pro-IL-1β precursor by caspase-1, which is activated via the NLRP3 inflammasome complex. The nuclear factor-κB (NF-κB) transcription factor is the master regulator of inflammatory responses. Brindle berry (Garcinia cambogia) has been widely used as health products for treating obesity and related metabolic disorders, but its active principles remain unclear. We previously found a series of polyisoprenylated benzophenones from brindle berry with anti-inflammatory activities. In this study we investigated whether 14-deoxygarcinol (DOG), a major polyisoprenylated benzophenone from brindle berry, alleviated adipose tissue inflammation and insulin sensitivity in high-fat diet fed mice. The mice were administered DOG (2.5, 5 mg · kg⁻¹ · d⁻¹, i.p.) for 4 weeks. We showed that DOG injection dose-dependently improved insulin resistance and hyperlipidemia, but not adiposity in high-fat diet-fed mice. We found that DOG injection significantly alleviated adipose tissue inflammation via preventing macrophage infiltration and pro-inflammatory polarization of macrophages, and adipose tissue fibrosis via reducing the abnormal deposition of extracellular matrix. In LPS plus nigericin-stimulated THP-1 macrophages, DOG (1.25, 2.5, 5 μM) dose-dependently suppressed the activation of NLRP3 inflammasome and NF-κB signaling pathway. We demonstrated that DOG bound to and activated the deacetylase Sirtuin 2, which in turn deacetylated and inactivated NLRP3 inflammasome to reduce IL-1β secretion. Moreover, DOG (1.25, 2.5, 5 μM) dose-dependently mitigated inflammatory responses in macrophage conditioned media-treated adipocytes and suppressed macrophage migration toward adipocytes. Taken together, DOG might be a drug candidate to treat metabolic disorders through modulation of adipose tissue remodeling.

白细胞介素 (IL)-1β 是脂肪组织炎症的罪魁祸首，进而导致肥胖个体的系统性炎症和胰岛素抵抗。 IL-1β 主要在单核细胞和巨噬细胞中产生，少量在脂肪细胞中产生，通过 caspase-1 裂解无活性的 pro-IL-1β 前体，caspase-1 通过 NLRP3 炎性体复合物激活。核因子-κB (NF-κB) 转录因子是炎症反应的主要调节因子。斑纹莓（ Garcinia cambogia ）已被广泛用作治疗肥胖和相关代谢紊乱的保健品，但其活性原理仍不清楚。我们之前从花斑莓中发现了一系列具有抗炎活性的聚异戊二烯基二苯甲酮。在这项研究中，我们研究了 14-脱氧山竹酚 (DOG)（一种来自花斑浆果的主要聚异戊二烯基二苯甲酮）是否可以减轻高脂饮食喂养小鼠的脂肪组织炎症和胰岛素敏感性。对小鼠施用DOG（2.5，5 mg·kg ^-1 ·d ^-1 ，腹膜内）4周。我们发现，狗注射液剂量依赖性地改善高脂饮食喂养小鼠的胰岛素抵抗和高脂血症，但不能改善肥胖。我们发现DOG注射液通过阻止巨噬细胞浸润和巨噬细胞的促炎极化来显着减轻脂肪组织炎症，并通过减少细胞外基质的异常沉积来显着减轻脂肪组织纤维化。在 LPS 加尼日利亚霉素刺激的 THP-1 巨噬细胞中，DOG（1.25、2.5、5 μM）剂量依赖性地抑制 NLRP3 炎性体和 NF-κB 信号通路的激活。 我们证明，DOG 结合并激活去乙酰化酶 Sirtuin 2，进而使 NLRP3 炎性体去乙酰化并失活，从而减少 IL-1β 的分泌。此外，DOG（1.25、2.5、5 μM）剂量依赖性地减轻巨噬细胞条件培养基处理的脂肪细胞中的炎症反应，并抑制巨噬细胞向脂肪细胞迁移。总而言之，DOG 可能是通过调节脂肪组织重塑来治疗代谢紊乱的候选药物。